8fey | pdb_00008fey
Solution structure of Pmu1a
Structural highlights
Publication Abstract from PubMedVenom-derived peptides targeting ion channels involved in pain are regarded as a promising alternative to current, and often ineffective, chronic pain treatments. Many peptide toxins are known to specifically and potently block established therapeutic targets, among which the voltage-gated sodium and calcium channels are major contributors. Here, we report on the discovery and characterization of a novel spider toxin isolated from the crude venom of Pterinochilus murinus that shows inhibitory activity at both hNa(V) 1.7 and hCa(V) 3.2 channels, two therapeutic targets implicated in pain pathways. Bioassay-guided HPLC fractionation revealed a 36-amino acid peptide with three disulfide bridges named mu/omega-theraphotoxin-Pmu1a (Pmu1a). Following isolation and characterization, the toxin was chemically synthesized and its biological activity was further assessed using electrophysiology, revealing Pmu1a to be a toxin that potently blocks both hNa(V) 1.7 and hCa(V) 3. Nuclear magnetic resonance structure determination of Pmu1a shows an inhibitor cystine knot fold that is the characteristic of many spider peptides. Combined, these data show the potential of Pmu1a as a basis for the design of compounds with dual activity at the therapeutically relevant hCa(V) 3.2 and hNa(V) 1.7 voltage-gated channels. Pmu1a, a novel spider toxin with dual inhibitory activity at pain targets hNa(V) 1.7 and hCa(V) 3 voltage-gated channels.,Giribaldi J, Chemin J, Tuifua M, Deuis JR, Mary R, Vetter I, Wilson DT, Daly NL, Schroeder CI, Bourinet E, Dutertre S FEBS J. 2023 Mar 13. doi: 10.1111/febs.16773. PMID:36912793[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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